Cardiac arrhythmias often occur as complications to cardiac diseases such as myocardial infarction and heart failure. In serious cases, arrhythmias give rise to ventricular fibrillation and can cause sudden death.
Although various antiarrythmic agents are now available on the market, those having both satisfactory efficacy and a high margin of safety have not been obtained. For example, antiarrythmic agents of Class I according to the classification scheme of Vaughan-Williams ("Classification of antiarrhythmic drugs", In: Cardiac Arrhythmias, edited by: E. Sandoe, E. FlenstedJensen, K. Olesen; Sweden, Astra, Sodertalje, pp449-472, 1981) which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (V.sub.max) are inadequate for preventing ventricular fibrillation. In addition, they have problems regarding safety, namely, they cause a depression of myocardial contractility and have a tendency to induce arrhythmias due to an inhibition of impulse conduction. Beta-adrenoceptor blockers and calcium antagonists which belong to Class II and IV, respectively, have a defect in that their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the antiarrhythmic agents of Class I.
Antiarrhythmic agents of Class III are drugs that cause a selective prolongation of the duration of the action potential without a significant depression of the V.sub.max. Available drugs in this class are limited in number. Examples such as sotalol and amiodarone have been shown to possess interesting Class III properties (Singh B. N., Vaughan Williams E. M. "A third class of anti-arrhythmic action: effects on atrial and ventricular intracellular potentials and other pharmacological actions on cardiac muscle, of MJ 1999 and AH 3747" Br. J. Pharmacol 39: 675-689, 1970; and Singh B. N., Vaughan Williams E. M, "The effect of amiodarone, a new, anti-anginal drug, on cardiac muscle", Br J. Pharmacol 39:657-667 1970.), but these are not selective Class III agents. Sotalol also possesses Class II effects which may cause cardiac depression and is contraindicated in certain susceptible patients. Amiodarone, also is not a selective Class III antiarrhythmic agent because it possesses multiple electrophysiological actions and is severely limited by side effects (Nademanee, K. "The Amiodarone Odessey", J. Am. Coil. Cardiol. 20:1063-1065, 1992.) Drugs of this class are expected to be effective in preventing ventricular fibrillation. Selective class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to inhibition of conduction of the action potential as seen with Class I antiarrhythmic agents.
Class III agents increase myocardial refractoriness via a prolongation of cardiac action potential duration. Theoretically, prolongation of the cardiac action potential can be achieved by enhancing inward currents (i.e. Na.sup.+ or Ca.sup.2+ currents; hereinafter I.sub.Na and I.sub.Ca respectively) or by reducing outward repolarizing potassium (K.sup.+) currents. The delayed rectifier (I.sub.K) K.sup.+ current is the main outward current involved in the overall repolarization process during the action potential plateau, whereas the transient outward (I.sub.to) and inward rectifier (I.sub.K1) K.sup.+ currents are responsible for the rapid initial and terminal phases of repolarization, respectively. Cellular electrophysiologic studies have demonstrated that I.sub.K consists of two pharmacologically and kinetically distinct K.sup.+ current subtypes, I.sub.Kr (rapidly activating and deactivating) and I.sub.Ks (slowly activating and deactivating). Class III antiarhythmic agents currently in development, including d-sotalol, dofetilide (UK-68,798), almokalant (H234/09), E-4031 and methanesulfonamide-N-[1'-6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4 -dihydro-4(R)-hydroxyspiro[2H-1-benzopyran-2,4'-piperidin]-6yl],(+)-,monoch loride predominantly, if not exclusively, block I.sub.Kr. Although, amiodarone is a blocker of I.sub.Ks (Balser J. R. Bennett, P. B., Hondeghem, L. M. and Roden, D. M. "Suppression of time-dependent outward current in guinea pig ventricular myocytes: Actions of quinidine and amiodarone. Circ. Res. 1991, 69: 519-529), it also blocks Na.sup.+ and Ca.sup.2+ currents, effects thyroid function, is as a nonspecific adrenergic blocker, and acts as an inhbitor of the enzyme phospholipase (Nademanee, K. "The Amiodarone Odessey". J. Am. Coil. Cardiol. 1992; 20:1063-1065). Therefore, its method of treating arrhythmia is uncertain.
Most Class III agents that are known to be in development predominantly block I.sub.Kr. These agents have a potential liability in that they have an enhanced risk of proarrhythmia at slow heart rates. For example, torsades de points has been observed when these compounds are utilized (Roden, D. M. "Current Status of Class III Antiarrhythmic Drug Therapy", Am J. Cardiol, 72:44B-49B, 1993.). This exaggerated effect at slow heart rates has been termed "reverse frequency-dependence", and is in contrast to frequency-independent or frequency-dependent actions (Hondeghem, L. M. "Development of Class III Antiarrhythmic Agents". J. Cadiovasc. Cardiol. 20(Suppl. 2):S17-S22).
A number of antiarrhythmic agents have been reported in the literature, such as those disclosed in:
(1) EP-A-O 397,121-A, PA1 (2) EP-A-O 300,908-A, PA1 (3) EP-A-O 307,121, PA1 (4) U.S. Pat. No. 4,629,739, PA1 (5) U.S. Pat. No. 4,544,654, PA1 (6) U.S. Pat. No. 4,788,196, PA1 (7) EP application No. 88302597.5, PA1 (8) EP application No. 88392598.3, PA1 (9) EP application No. 88302270.9, PA1 (10) EP application No. 88302600.7, PA1 (11) EP application No. 88302599.1, PA1 (12) EP application No. 88300962.3, PA1 (13) EP-A-O 235,752, PA1 (14) DE No. 3633977-A 1, PA1 (15) U.S. Pat. No. 4,804,662, PA1 (16) U.S. Pat. No. 4,797,401, PA1 (17) U.S. Pat. No. 4,806,555, PA1 (18) U.S. Pat. No. 4,806,536, PA1 (19) U.S. Pat. No. 5,032,598, PA1 (20) U.S. Pat. No. 5,032,604. PA1 1. 3(R)-(+)-1,3-dihydro-3-(2-indolecarbonylamino)-1-methyl-5-phenyl-2H-1,4-be nzodiazepin-2-one,. PA1 2. 3(S)-(-)-1,3-dihydro-3-(2-indolecarbonylamino)-1-methyl-5-phenyl-2H-1,4-be nzodiazepin-2-one,. PA1 3. N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-me thylphenyl)urea,. PA1 4. (R)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-( 3-methylphenyl)urea,. PA1 5. N-[3(R,S)-5-cyclohexyl-2,3-dihydro-1 -methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3-(isopropylsulfonylaminocarb onyl)phenyl]urea, example 2 herein. PA1 6. N,N-dimethyl-4-(3(R,S )-(((3-methylphenyl)amino)carbonyl)amino-1,3-dihydro-1-(2-methylpropyl)-2- oxo-1,4-benzodiazepin-5-yl)phenylmethylamine. PA1 7. (R)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one. PA1 8. N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(m-me thylphenyl)urea. PA1 9. (..+-..)-N-(2,3-dihydro-1-methyl-2-oxo-5-(4-pyridinyl)-1H-1,4-benzodiazepi n-3-yl-1H-indole-2-carboxamide. PA1 10. N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-4-methyl benzenesulfonamide. PA1 11. (R)-1-(2-(dimethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-3-((1-methyl- 1H-indole-3-yl)methyl)-2H-benzodiazepin-2-one. PA1 12. N-(2,3-dihydro-1-methyl-2-oxo-5-(4-morpholino)-1H-1,4-benzodiazepin-3-yl)- N'-3-methylphenylurea. PA1 a. (3RS)-N-(2,3-dihydro-1-methyl-2-oxo-S-Phenyl-1H-1,4-benzodiazepin-3-yl)-N' -(3-methylphenyl)-urea. PA1 b. (3R)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'- (3-methylphenyl)-urea. PA1 c. E-(+)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazeipn-3-y l)-N'-(3-methylphenyl)-urea. PA1 d. (+)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] -3-(3-chlorophenyl)propanamide. PA1 e. (3RS)-3-cyclohexyl-N-(2,3-dihydro-1-methyl-5-phenyl-2-thioxo-1H-1,4-benzod iazepin-3-yl)propanamide. PA1 f. (-)-3-Carbohexyl-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-4-oxido-5-phenyl-1H-1, 4-benzodiazepin-3-yl]propanamide. PA1 g. (+)-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-hexa mamide. PA1 h. (+)-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-pent anamide. PA1 i. N-[2,3-Dihydro-1-methyl-2-oxo-5-isopropyl-1H-1,4-benzodiazepin-3-yl]-3-cyu clohexyl]propanamide. PA1 j. N-[2,3-dihydro-1-methyl-2-oxo-5-isopropyl-1H-1,4-benzodiazepin-3-yl]-3-(2, 4-dichlorophenyl)propanamide. PA1 k. E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-y l]-3-(4-methoxyphenyl)-2-propenamide. PA1 l. (+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] propanamide. PA1 m. (+)-3-Cyclohexyl-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzod iazepin-3-yl]propanamide. PA1 n. (+)-N-[(3R)-2,3-Dihydro-1-methyl(-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl ]-2-(2,4-dichlorophenylthio)acetamide. PA1 o. (+)-N-[(3R)-7-Amino-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazep in-30-yl]-3-(2,4-dichlorophenyl)propanamide. PA1 p. (+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] -4-phenylbutanamide. PA1 q. (+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] -5-methyl-3-phenylisoxazole-4-carboxamide. PA1 r. N-[2,3-Dihydro-1-methyl-2-oxo-5-(4-methoxyphenyl)-1H-1,4-benzodiazepin-3-y l]-3-[2,4-dichlorophenyl]propanamide. PA1 s. N-[2,3-Dihydro-1-methyl-2-oxo-5-ethyl-1H-1,4-benzodiazepin-3-yl}-3-(2,4-di chlorophenyl)propanamide. PA1 t. E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-y l]-3-(2,4-dichlorophenyl)-2-propeneneamide.
Despite considerable progress there is still a need for new methods to treat cardiac arrhythmia. In an effort to overcome the side effects inherent in currently available antiarrhythmic agents, compounds that treat arrhythmia through blockade of I.sub.Ks are presented.